Constitutive systemic inflammation in Shwachman-Diamond Syndrome.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with increased risk of MDS/AML.
• While not primarily inflammatory, SDS involves conditions with immune dysfunctions.
• Previous studies showed hyperactivated STAT3/mTOR pathways and elevated IL-6 in SDS leukocytes.

Purpose of the Study:

• To investigate systemic inflammation in SDS patients.
• To analyze phosphoproteins in STAT3 and mTOR pathways in SDS lymphoblastoid cells (LCLs).
• To examine the secretomic profile of pro-inflammatory mediators in SDS plasma and LCLs.

Main Methods:

• Analysis of phosphoproteins, cytokines, chemokines, and growth factors in SDS patients and healthy donors using Bio-plex technology.
• MicroRNA profiling via next-generation sequencing (NGS).
• Validation of microRNA expression using RT-PCR and ddPCR.

Main Results:

• Dysregulation of ERK1/2 and AKT phosphoproteins confirmed interplay of STAT3 and mTOR pathways in SDS.
• Elevated plasma levels of soluble pro-inflammatory mediators were observed in SDS.
• Down-regulation of miR-181a-3p, a regulator of inflammatory pathways, was identified in SDS.

Conclusions:

• SDS pathophysiology involves complex interactions within STAT3 and mTOR pathways, influenced by inflammation.
• Elevated pro-inflammatory mediators and down-regulated miR-181a-3p contribute to constitutive inflammation in SDS.
• Findings suggest potential benefit of anti-inflammatory therapies for Shwachman-Diamond Syndrome.